Over the past decade, evidence has accumulated that mammalian integument, including human skin, is an important extrapituitary site of prolactin (PRL) expression and hormone activity, since both murine and human skin not only express functional receptors, but also PRL itself. This is well in line with the long-standing recognition that the mammary gland is an epidermally derived skin appendage, in whose development and remodelling during lactation PRL is appreciated to play an important role, and that PRL is known to impact on hair growth in several mammalian species. Since integumental structures far antedate the appearance of a pituitary gland during evolution, it is reasonable to assume that PRL functions in the skin of current day mammals are indicative of ancestral functions of this pleiotropic peptide hormone, some of which may still be conserved and operative in human skin. However, it remains unclear whether PRL generated in human skin is systemically released or primarily serves intracutaneous auto-/paracrine functions. Moreover, the functional significance of intracutaneous PRL expression in skin health and disease (e.g. psoriasis, lupus erythematosus) remains quite unclear.Here we summarize our own limited excursion into cutaneous PRL biology, which has helped to generate some intriguing pointers that guide future work at this interdisciplinary research frontier that borders on epithelial biology, neuroendocrinology and clinical dermatology. Following up our older findings on the hair cycle-dependent expression pattern and hair cycle-inhibitory effects of PRL in mice, we subsequently showed that PRL also inhibits the growth of male occipital scalp hair follicles (HFs). Yet, in female frontotemporal human HFs PRL has hair growth-stimulatory properties and also elicits a strikingly distinct gene expression response than in male HFs. Thus, quite like with androgens and estrogens, the response of human skin to PRL shows fundamental gender- and/or location dependent differences. Regarding the controls of PRL and PRLR expression in human skin, data from the organ culture of female human scalp HFs suggest that classical stimulators of pituitary PRL secretion, i.e. thyrotropin-releasing hormone (TRH) and 17-beta-estradiol, both of which are also produced by the pilosebaceous unit itself, upregulate intracutaneous PRL and PRLR expression, just as they do in the pituitary gland. Instead, dopamine, the dominant pituitary (inhibitory) control of PRL expression and secretion does not change the follicular expression of PRL protein in situ. Interestingly, the proinflammatory cytokine, interferon-gamma, increases PRL immunoreactivity in the epithelium of organ-cultured human HFs, while tumour necrosis factor -α decreases both PRL and PRLR protein expression in situ. This indicates that the central and peripheral regulation of PRL in humans, namely in the pituitary gland and the skin, shows important similarities, but is distinct. This may be important in inflammatory dermatoses (e.g. psoriasis, lupus erythematosus), and their management (e.g., with TNF-alpha antagonists).PRL has also surfaced as a novel neuroendocrine regulator of human keratin expression and epithelial stem cell biology in situ, since PRL differentially regulates a defined subset of keratins and keratin-associated proteins in human scalp HFs. For example, PRL up-regulates expression of keratins K5 and K14 and of the epithelial stem cell-associated keratins K15 and K19, whereas it inhibits K6 and K31 expression. Since a pure competitive PRL receptor antagonist alone also modulates keratin expression, “tonic stimulation” by endogenously generated PRL may be required for normal expression levels of selected keratins. Taken together with the recognized role of PRL as immunomodulator and in regulating epithelial cell proliferation/apoptosis/ electrolyte transport and preliminary evidence that PRL may negatively regulate selected aspects of wound healing, these recent insights into PRL as modulator of keratin expression and epithelial stem cell function in human skin and/or HFs underscore that the systematic exploration of PRL functions in human skin is likely to uncover novel, translationally relevant PRL functions in peripheral tissue physiology and pathology.